Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833

J Clin Invest. 1997 Nov 15;100(10):2430-6. doi: 10.1172/JCI119784.


Mice lacking mdr1-type P-glycoproteins (mdr1a/1b [-/-] mice) display large changes in the pharmacokinetics of digoxin and other drugs. Using the kinetics of digoxin in mdr1a/1b (-/-) mice as a model representing a complete block of P-glycoprotein activity, we investigated the activity and specificity of the reversal agent SDZ PSC833 in inhibiting mdr1-type P-glycoproteins in vivo. Oral PSC833 was coadministered with intravenous [3H]digoxin to wild-type and mdr1a/1b (-/-) mice. The direct excretion of [3H]digoxin mediated by P-glycoprotein in the intestinal mucosa of wild-type mice was abolished by administration of PSC833. Hepatobiliary excretion of [3H]digoxin was markedly decreased in both wild-type and mdr1a/1b (-/-) mice by PSC833, the latter effect indicating that in vivo, PSC833 inhibits not only mdr1-type P-glycoproteins, but also other drug transporters. Upon coadministration of PSC833, brain levels of [3H]digoxin in wild-type mice showed a large increase, approaching (but not equaling) the levels found in brains of PSC833-treated mdr1a/1b (-/-) mice. Thus, orally administered PSC833 can inhibit blood-brain barrier P-glycoprotein extensively, and intestinal P-glycoprotein completely. These profound pharmacokinetic effects of PSC833 treatment imply potential risks, but also promising pharmacological applications of the use of effective reversal agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency*
  • Administration, Oral
  • Animals
  • Bile / drug effects
  • Bile / metabolism
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / physiology*
  • Brain / metabolism*
  • Cyclosporins / administration & dosage
  • Cyclosporins / pharmacology*
  • Digoxin / blood
  • Digoxin / pharmacokinetics*
  • Drug Resistance, Multiple
  • Gastrointestinal Contents / chemistry*
  • Intestines / drug effects
  • Intestines / physiology
  • Liver / physiology
  • Mice
  • Mice, Knockout
  • Time Factors
  • Tissue Distribution


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cyclosporins
  • Digoxin
  • valspodar